This invention relates to aspartic acid derivatives and a method of peptide synthesis.
With recent developments in the method of analyzing extremely small quantities of components in living bodies, many physiologically active peptides have been discovered which are useful medically or as medicines. Since large quantities of these peptides are required for medical research and as medicines, it is important to develop a method of organic synthesis whereby they can be supplied economically and in large quantities.
In the meantime, instead of the conventional Boc method (B. Ridge, "Amino-Acids Peptides And Proteins", The Chemical Society, Vol. 6, p. 302 (1975)) whereby t-butoxycarbonyl (referred to as Boc) group is used for the protection of .alpha.-amino group and an expensive apparatus is used for the final deprotection with hydrogen fluoride, the Fmoc method (Carpino, et al., J. Am. Chem. Soc., Vol. 92, pp. 5748-5749 (1970) and Bodanszki, et al., J. Org. Chem., Vol. 45, pp. 72-76 (1980)) of using 9-fluorenylmethoxycarbonyl (referred to as Fmoc), which allows deprotection under a mildly basic condition, for the protection of .alpha.-amino group and trifluoroacetic acid which is a mild acid, for the final deprotection whereby peptides can be synthesized in a simple manner is coming to be frequently used. The present inventors have completed the present invention as a result of diligent studies by observing that, although the Fmoc method is an excellent method of synthesis, it can be applied only to a limited extent to the synthesis of peptides containing aspartic acid because of its deprotection method under a basic condition.
It has been known that the synthesis of aspartyl peptides is accompanied by a succinimide-forming side reaction whether the Boc method or the Fmoc method is used. Formation of succinimide is significant if the peptide contains an aspartyl-glycine or aspartyl-serine linkage and is particularly noteworthy under a basic condition. Although this is convenient for the Fmoc method according to which deprotection is carried out under a basic condition, it is not so for the synthesis of peptides containing aspartic acid. By either method, furthermore, it has been difficult to synthesize such peptides with high purity and at a high yield (Battersby, et al., J. Chem. Soc., pp 259-269 (1955) and Hanson, et al., ibid., 836-842 (1964)).